Integrating common and rare genetic variation in diverse human populations

Abstract

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called ‘HapMap 3’, includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of ≤5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

Genome‐wide association studies of multiple sclerosis

“…The development of genetic maps covering much of the genome led to linkage analyses in extended MS affected families from a number of countries, primarily of European ancestry 23, 24, 25, 26, 27, 28, 29, 30, 31, 32. These validated the HLA association but showed no significant linkage to loci outside the MHC.…”

“…The completion of the human genome sequencing project led to the development of complete catalogues of common genetic variation across the genome, and concomitant technologies to assay these variants in a cost‐effective and high‐throughput manner 25, 26. This technological development enabled the profiling of thousands of samples in a single study and prompted a shift away from family studies, where samples are necessarily limited and ascertainment challenging, to population‐based association studies comparing unrelated cases and controls 27.…”

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

“…The HapMap project, which was started in 2003[89], has genotyped four million Single Nucleotide Polymorphisms (SNPs) in 1301 individuals from eleven populations distributed across the world[90]. The data has provided an abundance of information on common SNPs and their association with human disease, but many variants, including disease-causing variants, that occur at a low allele frequency in the population have been missed.…”

Human population structure and the adaptive response to pathogen-induced selection pressures

“…Recent studies have made clear that relative to expectations for constantsized populations human sequence variation shows a strong excess of rare variants, most probably owing to population growth [64,65]. When designing mapping studies to discover novel resistance variants, we must keep these expectations in consideration.…”